The endoplasmic reticulum acetyltransferases ATase1/NAT8B and ATase2/NAT8 are differentially regulated to adjust engagement of the secretory pathway

AbstractN ε‐lysine acetylation of nascent glycoproteins within the endoplasmic reticulum (ER) lumen regulates the efficiency of the secretory pathway. The ER acetylation machinery consists of the membrane transporter, acetyl‐CoA transporter 1 (AT‐1/SLC33A1), and two acetyltransferases, ATase1/NAT8B and ATase2/NAT8. Dysfunctional ER acetylation is associated with severe neurological diseases with duplication ofAT ‐1/SLC33A1 being associated with autism spectrum disorder, intellectual disability, and dysmorphism. Neuron ‐specific AT‐1 overexpression in the mouse alters neuron morphology and function, causing an autism‐like phenotype, indicating that ER acetylation plays a key role in neurophysiology. As such, characterizing the molecular mechanisms that regulate the acetylation machinery could reveal critical information about its biology. By using structure‐biochemistry approaches, we discovered that ATase1 and ATase2 share enzymatic properties but differ in that ATase1 is post‐translationally regulated via acetylation. Furthermore, gene expression studies revealed that the promoters ofAT ‐1,ATase1, andATase2 contain functional binding sites for the neuron ‐related transcription factors cAMP response element‐binding protein (CREB) and the immediate early genes c‐FOS and c‐JUN, and thatATase1 andATase2 exhibit additional modes of transcriptional regulation relevant to aging and Alzheimer's disease. In vivo rodent gene expression experiments revealed...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research